Presence of High-risk HLA Genotype Is the Most Important Individual Risk Factor for Coeliac Disease Among At-Risk Relatives

Saana Paavola; Katri Lindfors; Laura Kivelä; Juliana Cerqueira; Heini Huhtala; Päivi Saavalainen Riku Tauschi; Katri Kaukinen; Kalle Kurppa


Aliment Pharmacol Ther. 2021;54(6):805-813. 

In This Article

Abstract and Introduction


Background: Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure.

Aims: To investigate the individual risk of coeliac disease among patients' relatives.

Methods: Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression.

Results: There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04–2.45) in index, and age 41–60 years (1.73, 1.10–2.73), being a sibling (1.65, 1.06–2.59) and having the high-risk genotype (3.22, 2.01–5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80–4.78) in multivariable analysis.

Conclusions: Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. identifier NCT03136731.


Coeliac disease is a gluten-driven chronic gastrointestinal condition affecting individuals with a predisposing human leucocyte antigen HLA-DQ2 and/or HLA-DQ8 haplogenotype.[1] Estimated prevalence of the disease is up to 1%-3% in general population, but currently, most of the affected patients remain unrecognised.[2–5] This substantial underdiagnosis could be improved by active testing of either specific at-risk groups or even the whole population with serum coeliac autoantibodies. At present, most authorities do not recommend untargeted screening mainly because of inconsistent data on the prognosis of unrecognised coeliac disease at the population level.[6–9] However, particularly, the first-degree (FDR) and, sometimes, also second-degree (SDR) relatives of patients are often considered to have a sufficiently high disease risk to justify screening.[9–13]

Selecting an optimal screening strategy is complicated by a wide variation in the reported family risk[14–16] possibly due to different poorly defined patient- and relative-related individual factors, such as age at screening, gender, HLA haplogenotype and degree of consanquinity.[1,16–23] Limited data on these factors make optimal timing of screening, testing of other than FDRs, and the benefits of genetic risk stratification debatable.[13,15,16,23] The heterogenous and often small study cohorts and different diagnostic outcomes in earlier studies further hamper the interpretation of the results and emphasise the need for additional evidence.[14] Besides optimised implementation of the screenings, better understanding of the individual risk factors could provide novel insights into pathogenesis. In fact, precise risk stratification in coeliac disease is becoming increasingly important as we may be entering the era of primary preventions.[24,25]

Here we aimed to study the impact of various index patient- and relative-related factors on the risk of coeliac disease. This was established by serological and genetic testing of a large and well-defined cohort of relatives of previously diagnosed coeliac disease patients.